Opioids remain the primary drugs of choice for the treatment of moderate to severe pain. In spite of their well accepted clinical efficacy, the use of opioid analgesics for the treatment of chronic or prolonged pain states is hampered by the development of tolerance to their antinociceptive effect. Many studies have focused on cellular mechanisms that drive the development of antinociceptive tolerance. While these changes are clearly relevant and important to observations made using intact "physiological" systems, our current level of understanding does not allow us to directly relate cellular mechanisms with opioid-induced changes at the systems level. Mechanistic interpretation of opioid antinociceptive tolerance in preclinical studies is particularly difficult as many substances have been shown to reverse established opioid tolerance. A similarity throughout substances that block antinociceptive tolerance is that they all inhibit endogenous systems that promote pain. From this perspective, pain might be viewed as a "physiological antagonist of antinociception" and thus, increased pain may manifest as "opioid tolerance". For this reason, we propose to synthesize and test analogues with dual activity. These analogues will act as antinociceptive agents at the mu and/or delta opioid receptor as well as inhibit an endogenous substance that promotes pain, substance P, by acting as an NK-1 antagonist. Specifically, with analogues being supplied from the chemistry core, the biochemical core will: 1) perform radioligand binding assays for the mu, de;ta, and kappa copioid receptors with goals to achieve high affinity binding, 2) perform in vitro bioassays to achieve a mu and/or delta opioid agonists, 3) perform NK-1, NK-2 and NK-3 tachykinin receptor radioligand binding to achieve selective and moderate to high affinity at NK-1 receptors, 4) perform in vitro IPl accumulation assays in order to achieve an NK-1 antagonist, 5) perform in vivo studies using the hot water tail flick antinociceptive assay in mice after spinal administration to achieve efficacious compounds, 6) perform in vivo substance P induced scratching tests administering analogues spinally in the presence of the general opioid antagonist naloxone to achieve an active NK-1 antagonist, 7) perform in vivo tests to determine if the analogues result in opioid-induced pain and antinociceptive tolerance after repeated spinal administration, 8) perform stability and blood brain barrier transport experiments to determine whether or not analogues are stable in the presence of serum enzymes and whether or not the analogues will enter into the CNS after systemic administration, and 9) perform in rive antinociceptive tests after acute systemic administration of analogues, as well as opioid-induced pain and antinociceptive tolerance studies after repeated systemic administrations of the analogues. Data obtained from the biochemical core will be used to focus the synthesis of efficacious antinociceptive peptides that lack antinociceptive tolerance by the chemical core.